The neurotrophins - brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4) - are important survival factors for the developing taste system. Preliminary data shows that altering the pattern of BDNF or NT4 expression disrupts targeting of the chorda tympani. Specifically, when BDNF or NT4 is over-expressed in the basal epithelium of transgenic mice, taste axons of the chorda tympani nerve are misdirected to inappropriate non-taste bud targets. The mechanism underlying this misdirection of chorda tympani fibers is unclear. The long-term goal of the proposed research is to elucidate the mechanisms by which BDNF and NT4 over expression disrupts target selection in the fungiform taste system. The Specific Aims of this application will test the following hypotheses: 1) BDNF and/or NT4 over- expression in the basal layer of epithelia misdirects chorda tympani fibers during initial target innervation; and 2) BDNF over-expression can only disrupt chorda tympani targeting during a defined prenatal critical period, and not during postnatal development. The proposed studies will use anatomical, in situ hybridization, and immunohistochemical methodologies to: 1) determine the onset of BDNF and NT4 over-expression; and 2) determine how over-expression of BDNF or NT4 in tongue epithelium correlates temporally and spatially with the development of altered patterns of chorda tympani innervation in BDNF and NT4 over-expressing mice. The proposed studies will also use an inducible transgenic model of BDNF overexpression in which transgene expression is regulated by the Cre recombinase. This model system will allow us to test whether the sensitivity of chorda tympani fibers to BDNF overexpression is limited to a prenatal critical period or also occurs in adult systems. These experiments will provide requisite knowledge for future studies that will examine: 1) the receptors and internal signaling pathways mediating chorda tympani responses to BDNF and NT4; 2) interactions between neurotrophins and other axonal guidance cues; and 3) whether the location of BDNF and NT4 expression directs axonal regeneration. Uncovering these mechanisms will provide new insights into how taste neurons select their correct targets during development and following injury.